The long term use of opioids for the control of chronic pain is complicated by several factors limiting the efficacy of this approach, e.g. tolerance, opioid-induced hyperalgesia (OIH), physical dependence and abuse. It has become clear over recent years that genetic differences between individuals influence the likelihood each of these problems will develop. Moreover, the interaction of genetic factors with environmental conditions has been recognized to influence the experience of pain, the likelihood of developing opioid addiction and the likelihood of response to pain and addiction therapies. The high prevalence of pain, opioid prescribing and substance abuse in the veteran population make this topic of high relevance to the VA. Genetic approaches applied to mice chronically treated with opioids have demonstrated that the 5-opioid, 22-adrenergic and 5-HT3 receptors control several chronic opioid response adaptations (tolerance, OIH, physical dependence and use reinforcement). The principal objectives of the proposed work are, 1) to define the mechanisms by which the 5-opioid, 22-adrenergic and 5-HT3 receptors control each the adaptations, 2) to identify gene X environment interactions using pain as the critical and clinically relevant environmental factor, and 3) to define the mechanisms by which genetic factors and pain interact to control clinically relevant chronic opioid response adaptations. The proposed work will use a vertically integrated set of experiments focusing on the careful measurement of behaviors in mice chronically treated with opioids and the complementary use of selective pharmacological agents, gene knockout animals and tissue-specific gene expression studies. Our gene expression studies will target selected tissues and genes with strong evidence for participation in controlling each of the adaptations of interest. The tissues include the dorsal root ganglia (DRGs), spinal cord, locus coeruleus and extended amygdale. The experiments focused on gene X environment interaction will take advantage of a model of chronic inflammation well established in the laboratory and of particular relevance to clinical situations where chronic opioid administration is used. That model is the Freund's complete adjuvant (CFA) model of chronic inflammation. Finally, the proposed studies go well beyond simple descriptions of genetic and environmental effects as these studies are directed at identifying specific signaling pathways as convergence points for both genetic and environmental factors in controlling how animals respond to the relatively sustained administration of opioids. In the longer term we hope to design therapies based on the manipulation of these genetic and environmental factors to more successfully manage chronic pain and addiction in veterans.